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Pharm Exam 1 > Kocarek - Pharmacogenetics > Flashcards

Kocarek - Pharmacogenetics Flashcards

1
Q

Pharmacogenetics/Pharmacogenomics definition:

A

study of genetically controlled variations in drug response, and includes both genetic polymorphisms and rare genetic defects that alter an individual’s drug response

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2
Q

Genetic Polymorphisms

A

a Mendelian or monogenic trait that exists in the population in at least two phenotypes, neither of which is rare (>1-2%)

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3
Q

What is used to treat acute lymphoblastic leukemia and what gene variation prevents metabolism and can be fatal?

A

6-mercaptopurine (6-MP) is used to treat childhood ALL.

1 in 300 children has a variant gene for thiopurine methyltransferase that prevents 6-MP metabolism; drug accumulates in those children and can be fatal

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4
Q

What is clopidogrel and what does it require for conversion to its active form?

A

clopidogrel (plavix) is an anti-platelet drug that is used in addition to aspirin to prevent CV events in high risk pts.

Requires metabolism by CYP2C19 for conversion to active form

Without CYP2C19, clopidogrel builds up, therefore you need to know if the pt is a CYP2C19 poor metabolizer

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5
Q

What is the cause of isoniazid-induced neuropathy in some individuals?

A

NAT2 deficiency

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6
Q

What causes prolonged apnea after succinylcholine?

A

pseudocholinesterase deficiency

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7
Q

What breaks down debrisoquine (anti-hypertensive used in 1975 by Dr. Robert Smith)? What is the product?

A

Debrisoquine is converted to 4-hydroxydebrisoquine (inactive metabolite) by CYP2D6

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8
Q

Ultrarapid metabolizer for debrisoquine

A

multiple copies of CYP2D6

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9
Q

How can one estimate the fraction of phenotypic variability that is attributable to genetic factors?

A

Twin studies - monozygotic vs. dizygotic

Multigenerational kindred studies - interfamily vs. intrafamily variability

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10
Q

Additive (Codominant) Traits

A

Most common pattern

No domination of one allele over the other

Gene dosage effect
o AA= 2 good alleles, 100% function
o Aa= 1 good allele and 1 mutant allele, 50% function
o Aa= 2 mutant alleles, little/no function

Ex: CYP2C19 poor metabolizer

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11
Q

Autosomal Recessive

A

Normal allele dominates over mutant allele
o AA= 100% function
o Aa= 100% function
o aa= little/no function

Ex: CYP2D6 poor metabolizer

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12
Q

Autosomal Dominant

A

Only those with both good alleles have normal activity
o AA=100% function
o Aa and aa= little/ no function

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13
Q

What is the recommended starting dose for warfarin determined by?

A

CYP2C9 - metabolizes and inactivates warfarin

VKORC1 - pharmacological target of warfarin

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14
Q

Major types of polymorphism (3)

A

Single nucleotide polymorphisms (SNPs)
Insertions/deletions (Indels)
Copy number variations (CNV)

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15
Q

Single nucleotide polymorphisms (SNPs)

A

One every few hundred

About 10 million SNPs

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16
Q

Copy number variations (CNV)

A

~10% of the genome
Segment of DNA in which a variable number of that segment has been found in one or more populations
Duplications, deletions, inversions
CYP2D6 duplications associated with ultrarapid metabolizer phenotype

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17
Q

cSNPs

Types:

A

SNPs in coding region

Non-synonymous (missense) - aa change
Synonymous (sense) - no aa change
Nonsense - stop codon

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18
Q

Polymorphisms in non-coding regions (4)

A

5’ and 3’ untranslated regions of mRNA

Promoter and enhancer regions of genes

Introns

Intergenic regions

19
Q

Polymorphisms in 5’ and 3’ untranslated regions of mRNA

A

may alter cis-elements that determine mRNA translatability or stability

20
Q

Polymorphisms in Promoter and enhancer regions of genes

A

may alter cis-elements that regulate gene transcription

21
Q

Polymorphisms in introns

A

When near exon-intron boundaries, may affect transcript splicing - would often introduce a frame shift and a premature stop codon

22
Q

Polymorphisms in intergenic regions

A

may affect DNA tertiary structure, interaction with chromatin and topoisomerases, or DNA replication

23
Q

Where are most of the SNPs?

A

most of the SNPs are within introns or intergenic regions.

24
Q

What does CYP3A5*3 indicate?

A

The CYP3A5*3 allele contains a SNP in intron 3 that creates an alternative splice site, which results in introduction of an early stop codon and production of an inactive protein.

25
Q

Haplotype

A

Haplotype - a set of SNPs on a single chromosome that is statistically associated

The particular combination of all variants that occurs together for a gene

(wiki) A combination of alleles (DNA sequences) at adjacent locations (loci) on a chromosome that are inherited together.

A gene is likely to have more than one SNP – the haplotype is the particular combination of all SNPs

26
Q

ABCB1 gene has SNPs at base pair 3421 (T or A) and 3435 (C or T), what are the possible haplotypes?

A 
The possible haplotypes would be:
• T3421C3435
• T3421T3435
• A3421C3435
• A3421T3435
27
Q

Linkage definition:

2 types:

A

Definition: The extent to which the genotypes at two genetic loci are independent of one another.

Linkage equilibrium – the genotype present at one locus is independent of the genotype at a second locus

Linkage disequilibrium – the genotypes at the two loci are not independent of one another

Note:In complete linkage disequilibrium, genotypes at two loci always occur together

28
Q

Penetrance

A

Penetrance: proportion of individuals carrying a variant allele that express an associated phenotype

29
Q

Clinical relevance of a polymorphism is determined by (4):

A

Frequency and penetrance of a variant allele

Narrowness of therapeutic index or sharpness of dose-response curve

Limited availability of alternative clearance pathways

Absence of alternative drugs

30
Q

What type of varient has the highest predicted risk to the phenotype?

A

Nonsense

31
Q

What types of genes are involved in pharmacogenetic traits?

A

Genes that encode determinants of a drug’s pharmacokinetics
o e.g., Drug-metabolizing enzymes, transporters

Genes that encode drug receptors and targets
o Variants with profound functional consequences may cause disease
phenotypes that cause negative selective pressure
o However, variants that cause more subtle changes can be maintained in a
population without causing disease but may cause variation in drug
response

Genes that are involved in the disease being treated but do not directly interact
with a drug (modifiers)

(determinants, receptor/target, disease but don’t interact with drug)

32
Q

Why is UGT1A1 important?
What happens with a UGT1A1 defect?
What are some genetic diseases attributable to UGT1A1?

A

it metabolizes bilirubin

hyperbilirubinemia

Specific genetic diseases
that are attributable to UGT1A1 polymorphisms include Crigler-Najjar syndrome types I
and II and Gilbert’s syndrome.

33
Q

What 2 enzymes catalyze N-acetylation?

Which one is the primary polymorphic one?

A

Two major enzymes catalyze N-acetylation– N-acetyltransferases 1 and 2 (NAT1 and NAT2)

NAT2 is primary one that is polymorphic

NAT1 was thought not to be polymorphic, but recent evidence suggests that it also exhibits genetic polymorphisms

34
Q

N-acetyltransferases 2 (NAT 2) catalyzes: (3 examples)

A

NAT2 catalyzes the N-acetylation of a large number of drugs and environmental chemicals: e.g., procainamide, caffeine, 4-aminobiphenyl (human bladder carcinogen)

• NAT2 shows considerable ethnic variation: Slow acetylators account for 90% in other groups

35
Q

Acetylation polymorphism: slow acetylators

Slow acetylation is associated with several clinically important consequences (3):

isoniazid tx:
sulfa drug tx:
arylamin carcinaogens:

A

Slow acetylators more prone to polyneuropathy during isoniazid treatment

Slow acetylators more likely to develop hemolytic anemia during treatment with sulfa drugs

Incidence of bladder cancer greater in slow acetylators exposed to arylamine carcinogens

36
Q

What is a consequence of fast acetylators?

A

“Fast” acetylators require larger doses to achieve a given desired effect

37
Q

Human acetylation polymorphism controlled by 4 major alleles at a single autosomal gene locus on:

Slow vs. Fast acetylation:
Dominance:

A

Human acetylation polymorphism controlled by 4 major alleles at a single autosomal gene locus on chromosome 8

o 3 alleles encode for slow activity; 1 allele encodes for fast activity
o Fast activity is dominant – an individual must have 2 slow alleles to be a slow acetylator

38
Q

How many ADH enzymes in humans? Classes? Which class is the major ethanol-metabolizing enzyme?

A

Humans have 7 ADH enzymes grouped into 5 classes (I-V)

o Class I enzymes are major ethanol-metabolizing enzymes

39
Q

Nomenclature:
ADH1 =
ADH2 =
ADH3 =

A

Nomenclature:
ADH1 = ADH1A, encodes α polypeptide
ADH2 = ADH1B, encodes β polypeptide
ADH3 = ADH1C, encodes γ polypeptide

40
Q

Comparison of ADHs in Caucasians, East Asians, and individuals of African descent

A

Majority of Caucasians (about 95%) have ADH21 allele; about 50% ADH31 and ADH3*2

Majority of Japanese, Chinese, and Koreans have ADH2*2 allele

ADH23 observed in ~15% of individuals of African descent; rest have ADH21;
ADH3*1 in ~95%

41
Q

Comparison between ADH22 and ADH21.

What other polymorphism may occur with ADH2*2?

A

Individuals with the ADH22 genotype metabolize ethanol more rapidly than do those with the ADH21. Faster ethanol metabolism results in
increased production of acetaldehyde, which is the toxic metabolite that causes alcohol induced
flushing.

Some individuals also have a polymorphism in the aldehyde dehydrogenase enzyme (ALDH2*2) that decreases its ability to convert the acetaldehyde into acetic acid. Since these individuals both produce more acetaldehyde and are less able to detoxify it, they are particularly prone to flushing.

42
Q

ADH Genotype/Isoenzyme

A

ADH21 - beta1beta2
ADH22 - beta2beta2
ADH2*3 - beta3beta3

43
Q

EtOH to Acetyl-CoA formula

A

EtOH –ADH–> Acetaldehyde (Toxic) –ALDH–>Acetic acid —-> Acetyl-CoA

44
Q

What ADH genotype has the highest/lowest Vmax?

A 
Highest = 400 min-1: ADH2*2
Lowest = 9 min-1: ADH2*1

Pharm Exam 1 (23 decks)

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